N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was recently reported as a biomarker for diagnosing Kawasaki disease (KD). The basal NT-proBNP level, however, gradually decreases with age. We investigated the usefulness of an age-stratified cutoff value of NT-proBNP for diagnosing KD. All the patients enrolled in this study visited Chonnam National University Hospital between December 2007 and March 2016. The KD groups consisted of 214 patients with complete KD and 129 patients with incomplete KD. The control group included 62 children with simple febrile illness but without heart disease. Laboratory data including NT-proBNP level were evaluated. Each group was divided into subgroups according to patient age (<6 months, 6–12 months, 12–24 months, and >24 months), and different cutoff values of NT-proBNP were calculated. The cutoff values of NT-proBNP used to diagnose total KD and incomplete KD were 762 and 762 pg/mL (<6 months), 310 and 310 pg/mL (6–12 months), 326 and 326 pg/mL (12–24 months), and 208 and 137 pg/mL (>24 months), respectively. In conclusion, age-stratified NT-proBNP is a useful biomarker for the differential diagnosis of KD in patients with a simple febrile illness.
Kawasaki disease (KD) is a systemic vasculitis that usually affects children and infants < 5 years of age [
Because KD can only be diagnosed based on clinical symptoms, the diagnosis and treatment of KD patients are sometimes delayed; this is especially true for patients with incomplete KD, which is characterized by an incomplete presentation of diagnostic clinical symptoms [
N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is an adjuvant marker used to diagnose KD, and many studies have illustrated its usefulness [
The two KD groups (incomplete and complete KD) included a total of 343 children who were diagnosed with KD and treated with IVIg at Chonnam National University Hospital between December 2007 and March 2016. Complete KD was diagnosed according to American Heart Association criteria suggested in 2017 [
SPSS (version 23.0; SPSS, Chicago, IL, USA) was used for the data analyses. Continuous variables are presented as means ± standard deviations. The chi-square test was used to assess the statistical significance of differences between the independent variables. To compare data among more than three groups, analysis of variance (ANOVA) was employed, followed by Tukey’s honestly significant difference post hoc test. When the homogeneity of variance was not present according to Levene’s test, Dunnett’s T3 was used for the post hoc test. To evaluate the correlation between two serologic factors, both Pearson’s test and Spearman’s rho test were utilized. The KD groups were evaluated by multinomial logistic regression including NT-proBNP, CRP, platelet count, and albumin as fixed effects. When the normal distribution was not assumed on the Shapiro-Wilk test, the Kruskal-Wallis test followed by the Bonferroni correction was used. The cutoff values for diagnosing KD were obtained using receiver operating characteristic (ROC) curve analysis.
The purpose of this study was explained in detail to each patient’s parent, who provided informed consent after careful consideration. Approval for the present study was obtained from the Institutional Review Board of Chonnam National University Hospital (protocol number I-2009-09-103). All data were treated confidentially.
Patient demographics are shown in Table
Demographic characteristics and laboratory findings at diagnosis in patients with complete Kawasaki disease (KD), incomplete KD, and simple febrile illness (control).
Complete KD | Incomplete KD | Control | ||||
---|---|---|---|---|---|---|
|
Value |
|
Value |
|
Value | |
Age (years) | 214 | 2.8 ± 1.8 | 129 | 2.3 ± 2.0 | 62 | 2.9 ± 2.7 |
Sex (boy/girl) | 214 | 136/78 | 129 | 75/54 | 62 | 47/15 |
Total fever duration (days) | 214 | 6.0 ± 1.8 | 129 | 6.3 ± 2.5 | 62 | 5.3 ± 4.5 |
Duration of fever until IVIg (days) | 214 | 4.2 ± 1.9 | 129 | 4.5 ± 2.5 | 62 | 4.8 ± 3.9 |
White blood cell (count/mm3) | 214 | 14,561 ± 4855 | 129 | 13,955 ± 5557 | 62 | 12,268 ± 4753† |
Neutrophil (%) | 213 | 66.3 ± 15.7 | 129 | 56.8 ± 17.3† | 62 | 56.0 ± 21.0† |
Hemoglobin (g/dL) | 214 | 11.4 ± 1.1 | 129 | 11.2 ± 1.2 | 62 | 11.5 ± 1.3 |
Platelet (×103/mm3) | 214 | 343 ± 104 | 129 | 370 ± 145 | 62 | 279 ± 97†,‡ |
Erythrocyte sedimentation rate (mm/h) | 89 | 64.3 ± 26.6 | 50 | 69.3 ± 32.8 | 21 | 34.7 ± 32.0†,‡ |
C-reactive protein (mg/dL) | 214 | 8.1 ± 5.3 | 129 | 7.0 ± 5.6 | 62 | 4.8 ± 5.0†,¶ |
Aspartate aminotransferase (U/L) | 212 | 92 ± 138 | 128 | 66 ± 104 | 62 | 85 ± 132 |
Alanine aminotransferase (U/L) | 212 | 111.3 ± 170.8 | 128 | 67.8 ± 112.9 |
62 | 63.4 ± 131.8 |
Total bilirubin (mg/dL) | 139 | 1.1 ± 1.4 | 82 | 0.7 ± 0.8 |
28 | 0.6 ± 0.4 |
Total protein (g/dL) | 198 | 6.4 ± 0.8 | 117 | 6.5 ± 0.7 | 61 | 6.5 ± 0.6 |
Albumin (g/dL) | 214 | 3.6 ± 0.6 | 129 | 3.7 ± 0.5 | 62 | 3.9 ± 0.4†,¶ |
Lactate dehydrogenase (U/L) | 81 | 623 ± 160 | 53 | 638 ± 276 | 24 | 745 ± 258 |
Creatine kinase (IU/L) | 181 | 151 ± 376 | 114 | 120 ± 248 | 60 | 272 ± 503¶ |
Creatine kinase-MB (ng/mL) | 206 | 7.3 ± 10.5 | 122 | 4.8 ± 8.3 | 57 | 12.2 ± 11.9†,‡ |
Myoglobin (ng/mL) | 130 | 25.4 ± 60.2 | 85 | 19.0 ± 18.6 | 26 | 74.0 ± 92.4†,‡ |
Troponin I (ng/mL) | 197 | 0.02 ± 0.04 | 115 | 0.01 ± 0.01 | 45 | 0.01 ± 0.01 |
N-terminal prohormone of brain natriuretic peptide (pg/mL) | 214 | 1785 ± 2858 | 129 | 1153 ± 1725 |
62 | 311 ± 400†,¶ |
IVIg: intravenous immunoglobulin; KD: Kawasaki disease. Data are shown as mean ± SD.
Laboratory findings at diagnosis in patients with complete and incomplete Kawasaki disease (KD) and simple febrile illness (control) by age.
Complete KD | Incomplete KD | Control | ||||
---|---|---|---|---|---|---|
|
Value |
|
Value |
|
Value | |
<6 months | ||||||
|
21 | 21 (9.8) | 25 | 25 (19.4) | 8 | 8 (12.9) |
Age (years) | 21 | 0.4 ± 0.1 | 25 | 0.3 ± 0.1 | 8 | 0.3 ± 0.2 |
White blood cell (count/mm3) | 21 | 13,776 ± 4361 | 25 | 16,460 ± 6412 | 8 | 13,338 ± 6342 |
Erythrocyte sedimentation rate (mm/h) | 13 | 42.7 ± 21.8 | 7 | 65.6 ± 17.6 | 3 | 37.3 ± 20.5 |
C-reactive protein (mg/dL) | 21 | 8.1 ± 5.9 | 25 | 8.7 ± 4.7 | 8 | 3.3 ± 2.7‡ |
N-terminal prohormone of brain natriuretic peptide (pg/mL) | 21 | 3404 ± 3844 | 25 | 1846 ± 1811 | 8 | 669 ± 660 |
6–12 months | ||||||
|
20 | 20 (9.3) | 22 | 22 (17.1) | 11 | 11 (17.7) |
Age (years) | 20 | 0.8 ± 0.2 | 22 | 0.7 ± 0.1 | 11 | 0.8 ± 0.2 |
White blood cell (count/mm3) | 20 | 16,360 ± 3960 | 22 | 13,250 ± 6981 | 11 | 10,982 ± 3631 |
Erythrocyte sedimentation rate (mm/h) | 10 | 75.3 ± 28.6 | 7 | 54.0 ± 34.9 | 2 | 2.0 ± 0.0 |
C-reactive protein (mg/dL) | 20 | 7.1 ± 4.6 | 22 | 4.7 ± 5.2 | 11 | 3.7 ± 4.6 |
N-terminal prohormone of brain natriuretic peptide (pg/mL) | 20 | 2241 ± 3322 | 22 | 882 ± 1381 | 11 | 301 ± 310† |
12–24 months | ||||||
|
39 | 39 (18.2) | 21 | 21 (16.3) | 12 | 12 (19.4) |
Age (years) | 39 | 1.6 ± 0.3 | 21 | 1.5 ± 0.3 | 12 | 1.6 ± 0.3 |
White blood cell (count/mm3) | 39 | 14,341 ± 4611 | 21 | 12,886 ± 4688 | 12 | 12,967 ± 3444 |
Erythrocyte sedimentation rate (mm/h) | 17 | 64.5 ± 23.8 | 7 | 59.6 ± 30.5 | 4 | 39.8 ± 38.2 |
C-reactive protein (mg/dL) | 39 | 6.4 ± 4.2 | 21 | 4.6 ± 4.4 | 12 | 4.5 ± 4.2 |
N-terminal prohormone of brain natriuretic peptide (pg/mL) | 39 | 1372 ± 1387 | 21 | 1297 ± 1951 | 12 | 398 ± 560†,¶ |
>24 months | ||||||
|
134 | 134 (62.6) | 61 | 61 (47.3) | 31 | 31 (50.0) |
Age (years) | 134 | 3.8 ± 1.5 | 61 | 4.0 ± 1.6 | 31 | 4.9 ± 2.5 |
White blood cell (count/mm3) | 134 | 14,479 ± 5096 | 61 | 13,551 ± 4657 | 31 | 12,177 ± 5166 |
Erythrocyte sedimentation rate (mm/h) | 49 | 67.8 ± 26.0 | 29 | 76.2 ± 34.9 | 12 | 37.8 ± 34.2 |
C-reactive protein (mg/dL) | 134 | 8.8 ± 5.5 | 61 | 7.9 ± 6.0 | 31 | 5.8 ± 5.8† |
N-terminal prohormone of brain natriuretic peptide (pg/mL) | 134 | 1583 ± 2863 | 61 | 916 ± 1675† | 31 | 188 ± 154†,¶ |
KD: Kawasaki disease. Data are shown as mean ± SD.
Laboratory data from the complete and incomplete KD groups and the febrile control group at the time of diagnosis are shown in Figure
Dot plots of white blood cells (a), neutrophil percentage (b), platelet count (c), erythrocyte sedimentation rate (d), C-reactive protein level (e), and serum albumin level (f) in patients with complete Kawasaki disease (cKD), incomplete KD (iKD), and febrile illness (control).
In addition to the common serum chemical studies, we evaluated alterations in NT-proBNP levels. In all ages combined, the mean NT-proBNP levels in the complete KD group (1785 ± 2858 pg/mL) and incomplete KD group (1153 ± 1725 pg/mL) were significantly higher than that in the control group (311 ± 400 pg/mL,
Dot plots of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in patients with complete Kawasaki disease (cKD), incomplete KD (iKD), and febrile illness (control) (a). NT-proBNP values by age (b). Black solid line depicts linear regression. #
Assessment of the associations between clinical markers and Kawasaki disease using multinomial logistic regression.
Clinical marker |
|
|
---|---|---|
N-terminal prohormone of brain natriuretic peptide | 30.52 | <0.001 |
C-reactive protein | 1.64 | 0.441 |
Platelet | 30.03 | <0.001 |
Albumin | 4.79 | 0.091 |
It has been reported that serum NT-proBNP is negatively correlated with a child’s age [
Dot plot of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in patients with complete Kawasaki disease (KD), incomplete KD, and febrile illness (control) according to age.
In patients < 6 months of age, the mean NT-proBNP level in the complete KD group (3404 ± 3844 pg/mL) was significantly higher than that in the control group (669 ± 660 pg/mL,
Based on Pearson’s correlation coefficient, we next postulated that the NT-proBNP level in younger patients with KD was also higher than that in older KD patients. The mean NT-proBNP level in the complete KD group < 6 months of age was higher than that in the group > 24 months of age (
Dot plot of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in different age groups in patients with complete Kawasaki disease (KD) (a), incomplete KD (b), and febrile illness (control) (c).
Because the NT-proBNP level decreases with age, there is a need for different cutoff values to diagnose KD by patient age; thus, we used ROC curves to determine these values (Table
Diagnostic cutoff values of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in patients with complete, incomplete, and total (complete and incomplete) Kawasaki Disease (KD) compared to patients with simple febrile illness.
Cutoff value of NT-proBNP(pg/mL) | Sensitivity (%) | Specificity (%) | |
---|---|---|---|
Complete KD | |||
<6 months | 821 | 71.4 | 75.0 |
6–12 months | 315 | 85.0 | 81.8 |
12–24 months | 330 | 74.4 | 75.0 |
>24 months | 255 | 73.1 | 77.4 |
All ages | 326 | 73.8 | 74.2 |
Incomplete KD | |||
<6 months | 762 | 76.0 | 75.0 |
6–12 months | 310 | 72.7 | 81.8 |
12–24 months | 326 | 81.0 | 75.0 |
>24 months | 137 | 70.5 | 54.5 |
All ages | 261 | 68.8 | 67.2 |
Total KD | |||
<6 months | 762 | 73.9 | 75.0 |
6–12 months | 310 | 78.6 | 81.8 |
12–24 months | 326 | 76.7 | 75.0 |
>24 months | 208 | 70.8 | 69.7 |
All ages | 289 | 71.7 | 71.9 |
The cutoff value in the total KD patient group of all ages was 289 pg/mL, with 71.7% sensitivity and 71.9% specificity (area under the curve (AUC) = 0.774). The cutoff value in the group aged < 6 months was 762 pg/mL, with 73.9% sensitivity and 75.0% specificity (AUC = 0.813). Similarly, the cutoff values in the other age groups (6–12 months, 12–24 months, and >24 months) were 310 pg/mL (sensitivity, 78.6%; specificity, 81.8%; AUC = 0.779), 326 pg/mL (sensitivity, 76.7%; specificity, 75.0%; AUC = 0.796), and 208 pg/mL (sensitivity, 70.8%; specificity, 69.7%; AUC = 0.782), respectively. Cutoff values were also obtained in the complete KD patient group. The cutoff value in the complete KD group of all ages was 326 pg/mL, with 73.8% sensitivity and 74.2% specificity (AUC = 0.795), while that in the group aged < 6 months was 821 pg/mL, with 71.4% sensitivity and 75.0% specificity (AUC = 0.810). The cutoff values in the other age groups (6–12 months, 12–24 months, and >24 months) were 315 pg/mL (sensitivity, 85.0%; specificity, 81.8%; AUC = 0.868), 330 pg/mL (sensitivity, 74.4%; specificity, 75.0%; AUC = 0.797), and 255 pg/mL (sensitivity, 73.1%; specificity, 77.4%; AUC = 0.836), respectively. Similar cutoff values were obtained in the incomplete KD patient group. The cutoff value in the incomplete KD group of all ages was 261 pg/mL, with 68.8% sensitivity and 67.2% specificity (AUC = 0.719), and the cutoff value in the group aged < 6 months was 762 pg/mL, with 76.0% sensitivity and 75.0% specificity (AUC = 0.815). The cutoff values in the other age groups (6–12 months, 12–24 months, and >24 months) were 310 pg/mL (sensitivity, 72.7%; specificity, 81.8%; AUC = 0.698), 326 pg/mL (sensitivity, 81.0%; specificity, 75.0%; AUC = 0.794), and 137 pg/mL (sensitivity, 70.5%; specificity, 54.5%; AUC = 0.665), respectively.
Because a definitive diagnostic test for KD does not exist, diagnosis depends on a combination of clinical and laboratory findings [
Pre-proBNP, an analog of NT-proBNP, consists of 134 amino acids and is transformed into proBNP (108 amino acids), which is released from cardiac myocytes into the bloodstream. It is then broken down into bioactive BNP (32 amino acids) and NT-proBNP (76 amino acids). Usually, NT-proBNP plays no function in the body, but it can be used to indirectly measure the level of bioactive BNP [
Here, we found that the mean NT-proBNP in complete and incomplete KD patients was significantly higher than that in simple febrile illness patients in all age-stratified subgroups. Also, the mean NT-proBNP in complete KD patients was higher than that in incomplete patients. Our data revealed that the cutoff values for diagnosing KD and incomplete KD were 289 pg/mL (71.7% sensitivity and 71.0% specificity) and 261 pg/mL (72.1% sensitivity and 74.2% specificity), respectively. Many previous studies suggested cutoff values for distinguishing KD or incomplete KD from simple febrile illness [
Lee et al. also investigated the cutoff level of NT proBNP that allowed them to distinguish 33 incomplete KD patients from 19 simple febrile illness patients. They proposed that an NT-proBNP cutoff value of 158 pg/mL provided a sensitivity of 81% and a specificity of 74% for the diagnosis of incomplete KD [
However, previous studies did not consider the natural changes that occur in NT-proBNP levels with age. Here, we considered patient age a confounder and evaluated the different cutoff values for each disease group and the age-stratified subgroup. In each patient group, the mean NT-proBNP level decreased as age increased. In all KD patients, the cutoff value of NT-proBNP was 289 pg/mL for all age groups and 762 pg/mL for those aged < 6 months. In the incomplete KD group, the cutoff value of NT-proBNP was 261 pg/mL in all ages and 762 pg/mL in those aged < 6 months. In children < 6 months of age, applying the same NT-proBNP cutoff value for diagnosing KD regardless of age resulted in a higher sensitivity but a significantly lower specificity. Therefore, the usefulness of NT-proBNP as a diagnostic marker for KD was decreased.
We also found that the age-stratified cutoff values for patients aged 6–12 months were not significantly different from those for patients aged 12–24 months, including in terms of sensitivity and specificity. Therefore, for diagnosing KD based on NT-proBNP level, dividing the patients into three groups by age (<6 months, 6–24 months, and >24 months) and applying different cutoff values are more useful.
There are a few limitations to our study. We used a retrospective design and included a relatively small number of simple febrile illness patients as the control group. The major enrollment criterion for the control group was the performance of an NT-proBNP test. However, because of its high cost and need for extra blood samples, we did not perform an NT-proBNP test on every child with febrile illness who visited our center. Furthermore, we found relatively low sensitivity and specificity of the cutoff values compared to those in previous studies, especially in the group of patients > 24 months with incomplete KD [
Here, we proposed cutoff values of NT-proBNP in different age groups that were useful for diagnosing complete and incomplete KD and distinguishing those conditions from simple febrile illness. For differentiating any form of KD from febrile illness, the cutoff values are 762 pg/mL (<6 months), 310 pg/mL (6–12 months), 326 pg/mL (12–24 months), and 208 pg/mL (>24 months). For diagnosing incomplete KD, the cutoff values are 762 pg/mL (<6 months), 310 pg/mL (6–12 months), 326 pg/mL (12–24 months), and 137 pg/mL (>24 months).
In conclusion, this is the first report of age-stratified measurements of NT-proBNP in patients with complete or incomplete KD and controls with simple febrile illness. Age-stratified NT-proBNP is a useful biomarker for the differential diagnosis of complete KD and incomplete KD from simple febrile illness.
The authors have no conflicts of interest to disclose.
Sang Hoon Lee, Eun Song Song, and Somy Yoon contributed equally to the study.
The authors thank Professor Hee-Young Shin for his assistance with the statistical analysis. This study was supported by Grant NRF-2015R1D1A1A01059017 from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea.